DOI
https://doi.org/10.25772/3KDG-2311
Author ORCID Identifier
0000-0003-1847-8857
Defense Date
2019
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Biomedical Engineering
First Advisor
Rebecca L. Heise
Second Advisor
Seth Weinberg
Third Advisor
Laszlo Farkas
Fourth Advisor
Christopher Lemmon
Fifth Advisor
Joao Soares
Abstract
Angiogenesis is a complex process coordinating cell migration, proliferation, and lumen formation. Changes to the microenvironment regulate angiogenesis through mechanotransduction and cytokine signals. In pulmonary hypertension, something in the process becomes abnormal, resulting in changes to the microenvironment and the formation of a glomerulus of dysfunctional capillaries, called a plexiform lesion. Endothelial cells, expressing CD117 (CD117+ EC clones) increase in the plexiform lesions of pulmonary hypertension, independent of pro-angiogenic VEGF signaling. We hypothesize that the mechanical environment and the macromolecular composition of the extracellular matrix, both, contribute to the aberrant angiogenesis. When we changed the mechanical environment, we changed the angiogenic potential and cellular phenotype of CD117+ Endothelial cell clones. Turbulent flow, pathologic substrate stiffness, and pathologic stretch increased Endothelial-to-mesenchymal markers, such as acta2, cnn1, snail, and slug in CD117+ EC clones while CD117- ECs showed minimal change. We perturbed the mechanical environment of CD117+ EC clones and identified changes in Bone Morphogenic Protein-2, an often overlooked pro-angiogenic cytokine. We coupled changes in the mechanical environment to Rho GTPase intracellular signaling, to predict how changes to the mechanotransduction would affect angiogenesis through a computational model. In our model of angiogenesis, we found vessel synchronicity to depend on both which cell undergoes mitosis, and also at which phase of GTPase cycling the cell undergoes mitosis. We believe changes to the GTPase cycling may be the mechanism linking mechanotransduction to the abnormal vessels found in pulmonary hypertension. We are the first group to look at the role of the ECM composition, independent of stiffness. Our results show diseased ECM composition alone leads to phenotypic changes indicative of PH progression. In conclusion, these results provide a possible cytokine implicated in the mechanotransduction of PH, established a computational model of angiogenesis which provides a mechanotransduction mechanism of disease progression, and established that the ECM composition alone is capable of phenotypic changes leading to disease progression.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
6-10-2019
Included in
Biological Engineering Commons, Biomaterials Commons, Cell Biology Commons, Molecular, Cellular, and Tissue Engineering Commons, Other Cell and Developmental Biology Commons